Process for the production of 5-hydroxyoxazolidinones

ABSTRACT

A process for the production of hydroxy-substituted oxazolidinones, particularly 5-hydroxyoxazolidinones, which are useful as intermediates in the synthesis of herbicidally active compounds, comprising treating a hydroxythiazolidinone with an oxidizing agent.

The present invention relates to a process for the production ofhydroxy-substituted oxazolidinones, particularly 5-hydroxyoxazolidinoneswhich are useful as intermediates in the synthesis of herbicidallyactive compounds.

Oxazolidinone compounds which are active as herbicides are known from WO94/13652 and WO 95/33719 (published after the priority date of thepresent application). These documents disclose inter alia compounds ofthe formula: ##STR1##

wherein Z is O, S or NR⁴ ;

W is O or S;

R¹ is hydrogen, or C₁ -C₁₀ hydrocarbyl or heterocyclyl having 3 to 8ring atoms either of which may optionally be substituted with halogen,hydroxy, SO₂ NR^(a) R^(b) (where R^(a) and R^(b) independently representhydrogen or C₁ -C₆ alkyl), SiR^(c) ₃ (where each R^(c) is independentlyC₁ -C₄ alyl or phenyl), cyano, nitro, amino, mono- and di-C₁ -C₆alkylamino, acylamino, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy, C₁ -C₆alkylthio, C₁ -C₆ alkylsufinyl, C₁ -C₆ alylsulfonyl, carboxy,carboxyamide (in which the groups attached to the N atom may be hydrogenor optionally substituted C₁ -C₁₀ hydrocarbyl), C₁ -C₆ alkoxycarbonyl oraryl;

R², R³ and R⁴ independently represent hydrogen or C₁ -C₄ alkyl;

n is 0 or 1;

Y is O, S or NR⁵ ;

R⁵ is hydrogen, hydroxy, CHO or NR⁶ R⁷, or C₁ -C₁₀ hydrocarbyl or O(C₁-C₁₀ hydrocarbyl) either of which may be substituted with up to twosubstituents selected from OR⁶, COR⁶, COOR⁶, OCOR⁶, cyano, halogen,S(O)_(p) R⁶, NR⁶ R⁷, nitro, NR⁶ COR⁷, NR⁶ CONR⁷ R⁸, CONR⁶ R⁷ andheterocyclyl;

R⁶, R⁷ and R⁸ independently represent hydrogen or C₁ -C₆ hydrocarbyloptionally substituted with one or more halogen atoms;

p is 0, 1 or 2;

alternatively, when Y is NR⁵ and either Z is NR⁴ or n is 0, R⁵ and R⁴ orR¹ may together form a bridge represented by the formula --Q¹ --Q² -- or--Q¹ --Q² --Q³ --, where Q¹, Q² and Q³ independently represent CR⁹ R¹⁰,═CR⁹, CO, NR¹¹, ═N, O or S;

R⁹ and R¹⁰ independently represent hydrogen, C₁ -C₄ alky, hydroxy orhalogen;

R¹¹ represents hydrogen or C₁ -C₄ alkyl;

A is an aromatic or heteroaromatic ring system optionally substitutedwith one or more substituents selected from halogen, C₁ -C₁₀hydrocarbyl, S(O)_(p) (C₁ -C₁₀ hydrocarbyl), cyano, nitro, SCN, SiR^(c)₃ (where each R^(c) is independently C₁ -C₄ alkyl or phenyl), COR¹²,CR¹² NOR¹³, NHOH, ONR¹² R¹³, SF₅, COOR¹², SO₂ NR¹² R¹³, OR¹⁴ and NR¹⁵R¹⁶ ; and in which any ring nitrogen atom may be quaternised oroxidised;

alternatively, any two substituents of the group A may combine to form afused 5- or 6-membered saturated or partially saturated carbocyclic orheterocyclic ring in which any carbon or quaternised nitrogen atom maybe substituted with any of the groups mentioned as substituents on A, aring carbon atom may form part of a carbonyl group or a nitrogen atommay be oxidised;

R¹² and R¹³ independently represent hydrogen or C₁ -C₁₀ hydrocarbyl;

R¹⁴ is hydrogen, C₁ -C₁₀ hydrocarbyl, SO₂ (C₁ -C₁₀ hydrocarbyl), CHO,CO(C₁ -C₁₀ hydrocarbyl), COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R¹³ ;

R¹⁵ and R¹⁶ independently represent hydrogen, C₁ -C₁₀ hydrocarbyl, O(C₁-C₁₀ hydrocarbyl), SO₂ (C₁ -C₁₀ hydrocarbyl), CHO, CO(C₁ -C₁₀hydrocarbyl), COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R¹³ ; and

any of the hydrocarbyl groups within the group A, whether thehydrocarbyl group is a group on its own or part of a larger group, mayoptionally be substituted with halogen, hydroxy, SO₂ NR^(a) R^(b) (whereR^(a) and R^(b) independently represent hydrogen or C₁ -C₆ alkyl),cyano, nitro, amino, mono- and di-C₁ -C₆ alkylamino, acylamino, C₁ -C₆alkoxy, C₁ -C₆ haloalkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, carboxy, carboxyamide (in which the groups attachedto the N atom may be hydrogen or C₁ -C₁₀ hydrocarbyl optionallysubstituted with halogen), C₁ -C₆ alkoxycarbonyl or aryl.

Key intermediates in the synthesis of oxazolidinone herbicides such asthose mentioned above are hydroxyoxazolidinones of the formula: ##STR2##

WO 94/13652 discloses general processes for the production ofoxazolidinones, for example, introducing an appropriate side chain in asuitable substituted phenyl derivative and cyclising the side chain toform the desired oxazolidinone moiety.

WO 95/33719 discloses processes for the production ofhydroxyoxazolidinones comprising:

a) reduction of the corresponding compound of the formula: ##STR3##wherein each R¹⁹ is independently benzyl or substituted benzyl. Thereduction is preferably a hydrogenation performed over a palladium orplatinum catalyst in the presence of an acid such as trifluoroaceticacid; or

b) reaction of the corresponding compound of the formula: ##STR4##wherein R²⁰ is C₁ -C₆ alkyl; with an acid such as hydrochloric acid inan organic solvent such as 1,4-dioxan.

We have now found a novel process for the production of a group ofhydroxyoxazolidinones which offers significant advantages over theprocesses known from the prior art.

According to the invention there is provided a process for theproduction of a hydroxyoxazolidinone of formula I: ##STR5##

wherein A is phenyl optionally substituted by one or more substituentsselected from halogen, C₁ -C₁₀ hydrocarbyl, S(O)_(p) (C₁ -C₁₀hydrocarbyl), cyano, nitro, SCN, SiR^(c) ₃ (where each R^(c) isindependently C₁ -C₄ alkyl or phenyl), COR¹², CR¹² NOR¹³, ONR¹² R¹³,SF₅, COOR¹², S₂ NR¹² R¹³, OR¹⁴ and NR¹⁵ R¹⁶ ;

alternatively, two substituents of the group A may combine to form afused 5- or 6-membered saturated or partially saturated carbocyclic orheterocyclic ring in which any carbon or quaternised nitrogen atom maybe substituted with any of the groups mentioned as substituents on A, aring carbon atom may form part of a carbonyl group or a nitrogen atommay be oxidised;

p is 0, 1 or 2;

R¹² and R¹³ independently represent hydrogen or C₁ -C₁₀ hydrocarbyl;

R¹⁴ is hydrogen, C₁ -C₁₀ hydrocarbyl, SO₂ (C₁ -C₁₀ hydrocarbyl), CHO,CO(C₁ -C₁₀ hydrocarbyl), COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R¹³ ;

R¹⁵ and R¹⁶ independently represent hydrogen, C₁ -C₁₀ hydrocarbyl, O(C₁-C₁₀ hydrocarbyl), SO₂ (C₁ -C₁₀ hydrocarbyl), CHO, CO(C₁ -C₁₀hydrocarbyl), COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R¹³ ; and

any of the foregoing hydrocarbyl groups, whether the hydrocarbyl groupis a group on its own or part of a larger group, may optionally besubstituted with halogen, hydroxy, SO₂ NR^(a) R^(b) (where R^(a) andR^(b) independently represent hydrogen or C₁ -C₆ alkyl), cyano, nitro,amino, mono- or di-C₁ -C₆ alkylamino, acylamino, C₁ -C₆ alkoxy, C₁ -C₆haloalkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆alkylsulfonyl, carboxy, carboxyamide (in which the groups attached tothe N atom may be hydrogen or C₁ -C₁₀ hydrocarbyl optionally substitutedwith halogen), C₁ -C₆ alkoxycarbonyl or aryl;

which process comprises the step of treating a hydroxythiazolidinone offormula II: ##STR6##

in which A is as defined for formula I; with an oxidising agent

The expression "C₁ -C₁₀ hydrocarbyl" in the foregoing definitions,whether the expression is used on its own or as part of a larger radicalsuch as, for example, O(C₁ -C₁₀ hydrocarbyl), is intended to includehydrocarbyl radicals of up to ten carbon atoms. Subclasses of suchhydrocarbyl radicals include radicals with up to four or up to sixcarbon atoms. The expression "hydrocarbyl" is intended to include withinits scope aliphatic, alicyclic and aromatic hydrocarbyl groups andcombinations thereof. It thus includes, for example, alkyl, alkenyl andalkynyl radicals; saturated and unsaturated cycloalkyl radicals e.g.cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl;the adamantyl radical and aromatic radicals e.g. phenyl.

The expression "heterocyclyl" in the foregoing definitions is intendedto include both aromatic and non-aromatic radicals containing N, O or S.Examples of aromatic heterocyclyl radicals include pyridyl, pyrimidinyl,triazinyl, thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl, andexamples of non-aromatic heterocyclyl radicals include partially andfully saturated variants of the above.

The expression "C₁ -C₆ alkyl" refers to fully saturated straight orbranched hydrocarbon chains having from one to six carbon atoms.Examples include methyl, ethyl n-propyl, iso-propyl, t-butyl andn-hexyl. Expressions such as "alkoxy", "cycloalkyl", "alkyithio","alkylsulfonyl", "alkylsulfinyl" and "haloalkoxy" should be construedaccordingly.

The expression "C₂ -C₆ alkenyl" refers to straight or branchedhydrocarbon chains having from two to six carbon atoms and at least onecarbon-carbon double bond. Examples include ethenyl, 2-propenyl and2-hexenyl. Expressions such as cycloalkenyl, alkenyloxy and haloalkenylshould be construed accordingly.

The expression "C₂ -C₆ alkynyl" refers to straight or branchedhydrocarbon chains having from two to six carbon atoms and at least onecarbon-carbon triple bond. Examples include ethynyl 2-propynyl and2-hexynyl. Expressions such as cycloalkenyl, alkynyloxy and haloalkenylshould be construed accordingly.

Subclasses of the above include alkyl, alkenyl and alkynyl groups withup to 4 or up to 2 carbon atoms.

In the context of the present specification the terms "aryl" and"aromatic ring system" refer to ring systems which may be mono-, bi- ortricyclic. Examples of such rings include phenyl, naphthalenyl,anthracenyl and phenanthrenyl.

In the context of the present specification, the term "heteroaromaticring system" refers to an aromatic ring system containing at least oneheteroatom and consisting either of a single ring or of two or morefused rings. Preferably, single rings will contain up to 4 and bicyclicsystems up to 5 heteroatoms which will preferably be chosen from N, Oand S. Examples of such groups include furyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,oxazolyl, isoxazolyl thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl,1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, 12,4,5-tetrazinyl, benzofuryl, benzisofuryl,benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl,benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl,pteridinyl and indolizinyl. Nitrogen atoms in the ring system may bequaternised or oxidised.

In the context of the present specification, the term "fused saturatedor partially saturated carbocyclic or heterocyclic ring system" refersto a fused ring system in which a 5- or 6-membered carbocyclic or N, Oor S containing heterocyclic ring, which is not of aromatic character,is fused to an aromatic or heteroaromatic ring system. Examples of suchring systems include benzoxazolinyl and benzodioxolyl.

Halogen atoms which the compounds of formula I may be substitutedinclude chlorine, bromine, fluorine and iodine.

The group A preferably represents phenyl optionally substituted with oneor more substituents selected from halogen, C₁ -C₁₀ hydrocarbyl and O(C₁-C₁₀ hydrocarbyl). More preferably A represents phenyl substituted byone or more substituents selected from halogen, C₁ -C.sub.₄ alkyl, C₁-C₄ haloalkyl, O(C₁ -C₄ alkyl) and O(C₁ -C₄ haloalkyl).

The reaction is preferably performed in a solvent comprising a mixtureof water and a water-miscible organic solvent, for example, a mixture ofwater and a lower alkanol. The lower alkanol may be for example methanolor ethanol.

The oxidising agent used in the process may be a periodate salt, e.g.sodium periodate. A preferred oxidising agent comprises a periodatesalt, e.g. sodium periodate, together with a catalytic amount of aruthenium salt. The ruthenium salt is preferably a halide salt and morepreferably the trichloride salt

The process according to the invention takes place at moderatetemperatures, for example, at temperatures in the range 0-100° C. orabove, e.g. temperatures in the range of from 20-50° C.

The oxazolidinones of formula I may be isolated by conventional methods,for example by diluting the reaction mixture with water and extractingwith a water-immiscible organic solvent, washing the organic extractwith an aqueous solution of sodium sulfite to remove any traces ofoxidising agent, drying and evaporating the organic extract The residuecomprising the crude oxazolidinone may be purified by conventionalmethods, for example by recrystallisation or chromatography e.g. onsilica gel.

The hydroxythiazolidinones of formula II required as starting materialsare either known, or may be made by conventional methods, for example asdescribed in WO 94113652.

As mentioned above, compounds of formula I are useful as intermediatesin the synthesis of herbicides, therefore, in a further aspect of theinvention there is provided a process for the production of a compoundof formula III: ##STR7##

wherein A is as defined for formula I;

Z is O, S or NR⁴ ;

W is O or S;

R¹ is hydrogen, or C₁ -C₁₀ hydrocarbyl or heterocyclyl having 3 to 8ring atoms either of which may optionally be substituted with halogen,hydroxy, SO₂ NR^(a) R^(b) (where R^(a) and R^(b) independently representhydrogen or C₁ -C₆ alkyl), SiR^(c) ₃ (where each R^(c) is independentlyC₁ -C₄ alkyl or phenyl), cyano, nitro, amino, mono- and di-C₁ -C₆alkylamino, acylamino, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy, C₁ -C₆alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, carboxy,carboxyamide (in which the groups attached to the N atom may be hydrogenor optionally substituted C₁ -C₁₀ hydrocarbyl), C₁ -C₆ alkoxycarbonyl oraryl;

R⁴ represents hydrogen or C₁ -C₄ alkyl;

n is 0 or 1;

Y is O, S or NR⁵ ;

R⁵ is hydrogen, hydroxy, CHO or NR⁶ R⁷, or C₁ -C₁₀ hydrocarbyl or O(C₁-C₁₀ hydrocarbyl) either of which may be substituted with up to twosubstituents selected from OR⁶, COR⁶, COOR⁶, OCOR⁶, cyano, halogen,S(O)_(p) R⁶, NR⁶ R⁷, nitro, NR⁶ COR⁷, NR⁶ CONR⁷ R⁸, CONR⁶ R⁷ andheterocyclyl;

R⁶, R⁷ and R⁸ independently represent hydrogen or C₁ -C₆ hydrocarbyloptionally substituted by one or more halogen atoms;

p is 0, 1 or 2;

alternatively, when Y is NR⁵ and either Z is NR⁴ or n is 0, R⁵ and R⁴ orR¹ may together form a bridge represented by the formula --Q¹ --Q² -- or--Q¹ --Q² Q³ --, where Q¹, Q² and Q³ independently represent CR⁹ R¹⁰,═CR⁹, CO, NR¹¹, ═N, O or S;

R⁹ and R¹⁰ independently represent hydrogen, C¹ -C₄ alkyl, hydroxy orhalogen; and

R¹¹ represents hydrogen or C₁ -C₄ alkyl;

the process comprising producing a compound of formula I by a processaccording to the invention and converting it to a compound of formulaIII by any suitable method.

Examples of methods for converting compounds of formula I to compoundsof formula III are described in WO 94/13652 and WO 95/33719 but anymethod may be used.

For example, a compound of formula I may be converted to a compound offormula III in which Y is O by reaction with a compound of formula R¹COCl, R¹ OCOCl, R¹ --N═CO═O or R¹ R⁴ NCOCl, thus giving rise tocompounds of formula m in which W is O and n is 0, Z is O, Z is NH and Zis NR⁴ respectively. Similarly, a compound of formula I may be convertedto a compound of formula m in which Y and Z are both O, by reaction witha compound of formula VI: ##STR8##

Compounds of formula m in which Y is O, W is S and Z is NH may beprepared by the reaction of a compound of formula I with a compound offormula R¹ ═N═C═S.

Compounds of formula I may be converted into compounds of formula V:##STR9##

wherein A is as defined for formula I and R²⁰ is chloro,methanesulfonyloxy or toluenesulfonyloxy. The compounds in which R²⁰ ismethanesulfonyloxy or toluenesulfonyloxy may be obtained by reactionwith methanesulfonyl chloride or toluenesulfonyl chloride as appropriatealthough, in some cases, the compound in which R²⁰ is chloro may beobtained, particularly in the reaction with methanesulfonyl chloride.

Compounds of formula V may be converted into compounds of formula VI:##STR10##

wherein R⁵ and A are as defined for formula III; by reaction with analkali metal azide, such as sodium azide, to give the equivalent azidecompound followed by reduction of the azide by any known method, forexample using a 1,3-propane dithiol in a basic solvent, to give theappropriate compound of formula VI.

Alternatively, a compound of formula V may be reacted with ammonia or anamine of formula NH₂ R⁵.

Compounds of formula VI may be converted to compounds of formula m inwhich Y is NR⁵ using the reaction conditions described above for theconversion of compounds of formula I to compounds of formula III.

Compounds of formula V in which R²⁰ is halogen may be converted tocompounds of formula VII: ##STR11##

wherein A is as defined for formula I; by reaction firstly with athioacid of formula VIII: ##STR12##

wherein R¹ is as defined for formula III; to give a compound of formulaIII in which Y is S and n is 0; followed by reaction with ammonia in aprotic solvent such as methanol. The compound of formula VII may beconverted to a compound of formula III using the reaction conditionsdescribed above for the conversion of compounds of formula I tocompounds of formula III.

Compounds of formula III may also be converted to other compounds offormula III. For example, bridged compounds of formula III in which Y isNR⁵, Z is NR⁴, and R⁴ and R⁵ form a bridge may be synthesised in avariety of ways which will be apparent to those skilled in the art.

The compounds of formula m are useful as herbicides and show activityagainst a broad range of weed species including monocotyledonous anddicotyledonous species. They show some selectivity towards certainspecies, and may be used, for example, as selective herbicides in soya,maize and rice crops. The compounds of formula III may be used on theirown to kill or severely damage plants, but are preferably used in theform of a composition comprising a compound of formula III in admixturewith a carrier comprising a solid or liquid diluent.

The invention is illustrated by the following Examples. In the examplesNMR refers to the proton nuclear magnetic resonance spectrum recorded at270 MHz in CDCl₃ unless otherwise stated.

EXAMPLE 1 3-(3,4-Dichlorophenyl)-5-hydroxyoxazolidin-4-one

A stirred solution of 3-(3,4-dichlorophenyl)-5-hydroxythiazolidin4-one(264 mg, prepared as in Example 1 of WO 94/13652) in methanol (5 ml) wastreated with a solution of sodium periodate (852 mg) in water (10 ml).More methanol (5 ml) was added to redissolve the cloudy precipitatewhich formed. Ruthenium trichioride (10 mg) was added, whereupon thesolution turned brown, became warm and a precipitate slowly formed. Theresultant slurry was stirred for 2 hours, then water (30 ml) was addedand the mixture extracted with ethyl acetate (3×20 ml). The combinedethyl acetate extracts were washed with saturated aqueous sodium sulfitesolution (2×20 ml), water (3×20 ml) and brine (20 ml), then dried(MgSO₄). Evaporation of the solvent under reduced pressure gave a yellowoil, which was purified by silica-gel chromatography, eluting with ethylacetate/hexane mixtures, then by high-pressure silica-gelchromatography, eluting with 60% ethyl acetate/hexane, to give the titlecompound as a white solid (52 mg).

NMR δ: 4.59 (1H,brs), 5.41(1H,d), 5.60 (1H,m), 5.65 (1H,s), 7.35-7.49(2H,m), 7.72 (1H,d);

MS: m/z 247 (M⁺)(EI).

EXAMPLE 2

5-Hydroxy-3-(3-trifluoromethoxyphenyl)oxazolidin-4one

Prepared according to the method of Example 1 from the correspondingthiazolidinone prepared as in Example 38 of WO 94/13652.

NMR δ: 5.08 (1H,brs), 5.43 (1H,d), 5.66 (1H,m), 5.69 (1H,s), 7.09(1H,m), 735-7.45 (2H,m), 7.58 (1H,m).

EXAMPLE 3 3-(3-Bromo-4-chlorophenyl)-5-hydroxyoxazolidin-4-one a)1-Chloro-2-bromo-4-nitrobenzene

Iron (0.35 g) was added to 1chloro-4-nitrobenzene (15.8 g) at 140° C.,bromine (2.8 ml) was added dropwise and the mixture heated to 140° C.for 1 hour. Two further additions of iron and bromine were made at 1hour intervals followed by a final addition of iron (0.07 g) and heatingto 140° C. for 1 hour. The reaction mixture was allowed to cool to roomtemperature, added to sodium metabisulfite solution (200 ml) and stirredfor 30 min. The solution was extracted with dichioromethane (×4), washedwith aqueous sodium metabisulfite and water then dried (MgSO₄) to givean oil which was used in the next step without further purification.

b) 3-Bromo-4-chloroaniline

A mixture of iron (17.9 g), ethanol (120 ml), water (80 ml) and conc.hydrochloric acid (1.5 ml) was heated to 70° C., this temperature wasmaintained during the addition of 1-chloro-2-bromo-4-nitrobenzene (21.0g) in ethanol (100 ml) over 25 min. The mixture was heated to reflux for11/4 hours before adjusting the pH to 9-10 with sodium hydroxidesolution. The mixture was filtered hot through Hyflo™ washing with hotethanol and water. The mixture was concentrated, dichloromethane addedand the organic solution washed with water then dried (MgSO₄). Theproduct was purifed by silica gel chromatography then recrystalised fromether/hexane to give the sub-title compound as a solid.

NMR δ: 3.70 (2H,s), 6.52-6.58 (1H,m), 6.93-6.95 (1H,d), 7.16-7.20(1H,d).

c) 3-(3-Bromo-4-chlorophenyl)thiazolidin-4-one

Thioglycolic acid (8.65 g) and 37% aqueous formaldehyde (4.6 ml) wasadded to a stirred solution of 3-bromo-4-chloroaniline (9.73 g) intoluene (50 ml). The mixture was heated to reflux and the watercollected in a Dean and Stark apparatus. After 3 hours the mixture wascooled, diluted with toluene then washed with aqueous sodium hydroxideand water. The organic layer was dried (MgSO₄) and concentrated to givethe subtitle compound as a solid.

NMR δ: 3.72-3.74 (2H,m), 4.78-4.80 (2H,m), 7.38-7.50 (2H,m), 7.76-7.78(1H,m).

d) 343-Bromo-4-chlorophenyl)-5-chlorothiazolidin-4-one

Sulfurylchloride (3.83 g) was added over 1 min to a stirred suspensionof 3-(3-bromo-4-chlorophenyl)thiazolidin-4-one (7.8 g) in drydichloromethane (100 ml) at 0° C. The mixture was stirred at 0° C. for11/2 hours then concentrated and the resulting solid triturated withhexane to give the subtitle compound as a solid.

NMR δ: 4.65-4.69 (1H,d), 5.17-5.21 (1H,d), 5.76 (1H,s), 7.40-7.54(2H,m), 7.82-7.84 (1H,m).

e) 3-3-Bromo-4-chlorophenyl)-5-hydroxythiazolidin-4-one

Dilute hydrochloric acid (50 ml) was added to solution of3-(3-bromo-4-chlorophenyl)-5-chlorothiazolidin-4-one in THF (50 ml) andstirred at room temperature for 1 hour. The mixture was extracted withethyl acetate (×2) and the organic extracts washed with water, dried(MgSO₄) and concentrated to give the sub-title compound as an orangegum.

NMR δ: 4.63-4.67 (1H,d), 4.97-5.01 (1H,d), 5.70 (1H,s), 7.39-7.50(2H,m), 7.78-7.80 (1H,d).

f) 3-(3-Bromo-4-chlorophenyl)-5-hydroxyoxazolidin-4-one

Sodium periodate (14.2 g) was dissolved in water (175 ml) and rutheniumtrichloride (0.7 g) added to give a black solution. The solution wasstirred during the addition of3-(3-bromo-4-chlorophenyl)-5-hydroxythiazolidin-4-one (7.85 g) inmethanol (35 ml) over 5 min, the reaction vessel was cooled in an icebath to control the resulting exotherm. The mixture was stirred for 1hour before quenching with sodium metabisulfite. The mixture wasextracted with ethyl acetate and the combined organic extracts washedwith aqueous sodium metabisulfite solution and water, then dried(MgSO₄). Evaporation of the solvent under reduced pressure gave a gumwhich was triturated with dichloromethane to give the title compound asa grey solid (1.13 g), m.p. 139-140° C.

NMR δ: 5.36-5.38 (1H,d), 5.50-5.60 (2H,m), 6.85-6.89 (1H,d), 7.44-7.54(2H,m), 7.89-7.91 (1H,m).

EXAMPLE 4

The following compounds were prepared according to the relevant parts ofthe method of Example 3:

a) 3-(3-Difluoromethoxyphenyl)-5-hdroxyoxazolidin-4-one

NMR δ: 4.90 (1H,brs), 5.44 (1H,d), 5.62-5.67 (2H,m), 6.54 (1H,t), 7.00(1H,dd), 7.29 (1H,m), 7.39 (1H,t), 7.49 (1H,m).

b) 3-(3-Bromo-4-fluorophenyl)-5-hydroxyoxazolidin-4-one

NMR δ: 5.00 (1H,brs), 5.40-5.42 (1H,d), 5.59-5.63 (1H,m), 5.66 (1H,s),7.12-7.18 (1H,t), 7.42-7.50 (1H,m), 7.78-7.82 (1H,m).

c) 3-(3,5-Dichloro-4-fluorophenyl)-5-hydroxyoxazolidin-4-one

NMR δ: 4.75 (1H,brs), 5.49-5.51 (1H,d), 5.58-5.66 (2H,m), 7.56-7.60(2H,d).

d) 3-(3-Chlorolphenyl)-5-hydroxyoxazolidin-4-one

NMR δ: 4.50 (1H,brs), 5.40 (1H,d), 5.60 (2H,m), 7.20-7.40 (3H,m), 7.60(1H,t).

Thiazolidinone starting material prepared as in Example 5 of WO94/13652.

e) 3-(3,5-Dichlorophenyl)-5-hydroxyoxazolidin-4-one

NMR δ: 4.30 (1H,brs), 5.40 (1H,d), 5.60 (1H,d), 5.65 (1H,s), 7.20(1H,t), 7.50 (2H,d).

Thiazolidinone starting material prepared as in Example 6 of WO94/13652.

f) 3-(3-Chloro-4-fluorophenyl)-5-hydroxyoxazolidin-4-one

NMR δ: 4.85 (1H,brs), 5.40 (1H,d), 5.60 (1H,d), 5.65 (1H,s), 7.15(1H,t), 7.40 (1H,dt), 7.70 (1H,dd).

Thiazolidinone staring material prepared as in Example 7 of WO 94/13652.

g) 5-Hydroxy-3-(3-trifluoromethylphenyl)oxazolidin-4-one

NMR δ: 4.20 (1H,brs), 5.50 (1H,d), 5.63-5.70 (2H,m), 7.45-7.58 (2H,m),7.75-7.82 (2H,m).

Thiazolidinone starting material prepared as in Example 2 of WO94/13652.

EXAMPLE 5 Conversion of a Compound of Formula I into a Compound ofFormula III5-t-Butylcarbamoyloxy-3-(3-trifluoromethylphenol)oxazolidin-4-one

t-Butylisocyanate (1.77 g) was added to a sired solution of the compoundof Example 4g) (4.41 g) in dichloromethane (20 ml). Triethylamine (1.81g) was then added dropwise over 25 min. The resulting brown solution wasstirred at room temperature for 21/2 hours then left to stand overnight.The solvent was evaporated under reduced pressure to give a brown solidwhich was purified by flash chromatography using ethyl acetate/hexane2:8 as elutant. The resulting solid was triturated with hexane to givethe title compound as a white solid (3.49 g), mp. 122.4-123.8° C.

NMR δ: 1.35 (2H,m), 4.88 (1H,brs), 5.53 (1H,d), 5.65 (1H,m), 6.20(1H,s), 7.52 (2H,m), 7.80 (2H,m).

We claim:
 1. A process for the production of a hydroxyoxazolidinone offormula I: ##STR13## wherein A is phenyl optionally substituted by oneor more substituents selected from halogen, C₁ -C₁₀ hydrocarbyl,S(O)_(p) (C₁ -C₁₀ hydrocarbyl), cyano, nitro, SCN, SiR^(c) ₃ (where eachR^(c) is independently C₁ -C₄ alkyl or phenyl), COR¹², CR¹² NOR¹³, ONR¹²R¹³, SF₅, COOR¹², SO₂ NR¹² R¹³, OR¹⁴ or NR¹⁵ R¹⁶ ;alternatively, twosubstituents may combine to form a fused 5- or 6-membered saturated orpartially saturated carbocyclic or heterocyclic ring in which any carbonor quaternised nitrogen atom may be substituted with any of the groupsmentioned as substituents on A, a ring carbon atom may form part of acarbonyl group or a nitrogen atom may be oxidised; p is 0, 1 or 2; R¹²and R¹³ independently represent hydrogen or C₁ -C₁₀ hydrocarbyl; R¹⁴ ishydrogen, C₁ -C₁₀ hydrocarbyl, SO₂ (C₁ -C₁₀ hydrocarbyl), CHO, CO(C₁-C₁₀ hydrocarbyl), COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R¹³ ; R¹⁵ and R¹⁶independently represent hydrogen, C₁ -C₁₀ hydrocarbyl, O(C₁ -C₁₀hydrocarbyl), SO₂ (C₁ -C₁₀ hydrocarbyl), CHO, CO(C₁ -C₁₀ hydrocarbyl),COO(C₁ -C₁₀ hydrocarbyl) or CONR¹² R³ ; and any of the foregoinghydrocarbyl groups, whether the hydrocarbyl group is a group on its ownor part of a larger group, may optionally be substituted with halogen,hydroxy, SO₂ NR^(a) R^(b) (where R^(a) and R^(b) independently representhydrogen or C₁ -C₆ alkyl), cyano, nitro, amino, mono- or di-C₁ -C₆alkylamino, acylamino, C₁ -C₆ alkoxy, C₁ -C₆ haloalkoxy, C₁ -C₆alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, carboxy,carboxyamide (in which the groups attached to the N atom may be hydrogenor C₁ -C₁₀ hydrocarbyl optionally substituted with halogen), C₁ -C₆alkoxycarbonyl or aryl; which process comprises the step of treating ahydroxythiazolidinone of formula II: ##STR14## in which A is as definedfor formula I; with an oxidising agent.
 2. A process according to claim1, wherein the oxidising agent comprises a periodate salt and acatalytic amount of a ruthenium salt.
 3. A process according to claim 2,wherein the oxidising agent is sodium periodate.
 4. A process accordingto claim 2, wherein the ruthenium salt is a halide.
 5. A processaccording to claim 4, wherein the ruthenium salt is rutheniumtrichloride.
 6. A process according to claim 1, which is performed in asolvent comprising a mixture of water and a water-miscible organicsolvent.
 7. A process according to claim 6, wherein the water-miscibleorganic solvent is methanol or ethanol.
 8. A process according to claim1, wherein A represents phenyl optionally substituted with one or moresubstituents selected from halogen, C₁ -C₁₀ hydrocarbyl and O(C₁ -C₁₀hydrocarbyl).
 9. A process according to claim 8, wherein A representsphenyl substituted with one or more substituents selected from halogen,C₁ -C.sub.₄ alkyl, C₁ -C₄ haloalkyl, O(C₁ -C₄ alkyl) and O(C₁ -C₄haloalkyl).
 10. A process for the production of a compound of formulaIII: ##STR15## wherein A is as defined for formula I in claim 1; Z is O,S or NR⁴ ;W is O or S; R¹ is hydrogen, or C₁ -C₁₀ hydrocarbyl orheterocyclyl having 3 to 8 ring atoms either of which may optionally besubstituted with halogen, hydroxy, SO₂ NR^(a) R^(b) (where R^(a) andR^(b) independently represent hydrogen or C₁ -C₆ alkyl), SiR^(c) ₃(where each R^(c) is independently C₁ -C₄ alkyl or phenyl), cyano,nitro, amino, mono- and di-C₁ -C₆ alkylamino, acylamino, C₁ -C₆ alkoxy,C₁ -C₆ haloalkoxy, C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl C₁ -C₆alkylsulfonyl, carboxy, carboxyamide (in which the groups attached tothe N atom may be hydrogen or optionally substituted C₁ -C₁₀hydrocarbyl), C₁ -C₆ alkoxycarbonyl or aryl; R⁴ represents hydrogen orC₁ -C.sub.₄ alkyl; n is 0 or 1; Y is O, S or NR⁵ ; R⁵ is hydrogen,hydroxy, CHO or NR⁶ R⁷, or C₁ -C₁₀ hydrocarbyl or O(C₁ -C₁₀ hydrocarbyl)either of which may be substituted with up to two substituents selectedfrom OR⁶, COR⁶, COOR⁶, OCOR⁶, cyano, halogen, S(O)_(p) R⁶, NR⁶ R⁷,nitro, NR⁶ COR⁷, NR⁶ CONR⁷ R⁸, CONR⁶ R⁷ and heterocyclyl; R⁶, R⁷ and R⁸independently represent hydrogen or C₁ -C₆ hydrocarbyl optionallysubstituted by one or more halogen atoms; p is 0, 1 or 2; alternatively,when Y is NR⁵ and either Z is NR⁴ or n is 0, R⁵ and R⁴ or R¹ maytogether form a bridge represented by the formula --Q¹ --Q² -- or --Q¹--Q² --Q³ --, where Q¹, Q² and Q³ independently represent CR⁹ R¹⁰, ═CR⁹,CO, NR¹¹, ═N, O or S; R⁹ and R¹⁰ independently represent hydrogen, C₁-C₄ alkyl, hydroxy or halogen; and R¹¹ represents hydrogen or C₁ -C₄alkyl; the process comprising producing a compound of formula I by aprocess according to claim 1 and converting it to a compound of formulaIII.